Abstract
I first met Professor Ōmura, Distinguished Emeritus Professor, at The Kitasato Institute (Kitaken) when I was 28 years old. Since then, he has been my respectful supervisor as well as mentor. Looking back on those memories, I am deeply honored to write about the discovery and development of avermectin.
The history of The Kitasato Institute and the Ōmura Research Group
“Kitaken” was founded 100 years ago by Dr. Shibasaburo Kitasato with the motto “practical science.” There are two distinct objectives of Kitaken that both relate to the overarching theme of infectious diseases. The first is vaccine development, a goal extending from the immunizations pioneered by Dr. Kitasato. The second aim is chemotherapy, under which Dr. Sahachiro Hata discovered the syphilis drug Salvarsan and Dr. Tojyu Hata discovered the antibiotic leucomycin and the anticancer drug mitomycin.
For financial reasons in 1977, the Kitaken Board of Trustees decided to close the Laboratory for Antibiotics that Dr. Tojyu Hata had handed down to Prof. Ōmura. Prof. Ōmura could not accept the end of the laboratory given its profound history, so he strongly proposed that the laboratory be managed as financially self-sufficient and received approval from the Board. All expenses incurred from research activities—the salaries of the researchers: myself, Dr. Ruiko Oiwa, Dr. Yoko Takahashi, and Dr. Rokuro Masuma; the research students; and even rental of the laboratory space—were paid to Kitaken with money received from outside sources. July 7 1977 was the day Prof. Ōmura and Director Zenjiro Kitazato entered into the New Antibiotics Research Group Memorandum. Even today, Prof. Ōmura’s devotion to the lab continues to inspire me.
The Ōmura Research Group (Ōmura Grp.) was a collaborative group between the Laboratory for Antibiotics at Kitaken and Prof. Ōmura’s Laboratory of Microbial Chemistry in the School of Pharmaceutical Sciences at Kitasato University. The goal of the research was to “discover novel drugs of microbial origin that can be useful to mankind,” and much of the effort was devoted to screening micro-organisms. The Ōmura Grp. consisted of three subgroups to allocate research activities: (1) separation, culture, breeding, and preservation of micro-organisms; (2) separation, purification, structure determination, and evaluation of the activity of chemical compounds; and (3) organic synthesis and chemical modification. Guided by the talents of Prof. Ōmura, this system never faltered.
However, although Kitaken could manufacture and sell vaccines, medicines such as antibiotics required collaboration with industry partners. When they decided to bring in research funding, they also had to consider who they would choose for a partner company.
Industry–academia collaborations are commonplace nowadays, but back then, they were frowned upon by Kitaken and other academic institutions. Many companies, including Merck & Co. and Japanese companies such as Kyowa Hakko, Asahi Kasei, and Toyo Jozo, agreed to research partnerships at Ōmura’s request. In the joint research contract, Kitaken received funding from the companies and was the applicant for patents while the partner company received an exclusive license to the product and paid for the patent application and maintenance, which was called the “Ōmura System.”
Joint research with Merck & Co. and the discovery of avermectin
Joint research with Merck & Co. continued for 20 years with a focus on screening for antiparasitic agents, animal growth promoters, and other veterinary drugs. They divided the responsibilities between the two entities: Kitaken conducted research in vitro, and Merck & Co. tackled in vivo studies. Before commencing research, Prof. Ōmura and Dr. B. Woodruff at Merck & Co (a student of S. A. Waksman, the discoverer of streptomycin) spent 10 long days in a hotel negotiating the action plan and the final contract.
The Kitaken Ōmura Grp. strove to collect a diverse selection of actinomycetes originating from soil by reading the “face” of the micro-organism in the slant culture. Each strain was cultivated by liquid culture in multiple media. Antibacterial tests of the medium were performed at Kitaken, after which many actinomycetes and their data were sent to Merck & Co. In screening for antiparasitic properties, candidates were evaluated in vivo using procedures constructed by Dr. W. Campbell at Merck & Co., who received the Nobel Prize together with Prof. Ōmura. Mice were infected with Nematospiroides dubus （now called Heligmosomoides polygyrus, “dubius”） and then screening proceeded by administering the culture supernatant of the actinomycetes from the Ōmura Grp.
One day, Merck & Co. reported to Prof. Ōmura that strain OS-3153 (OS, for “Ōmura Satoshi,” is the naming convention for actinomycetes isolated in the Ōmura laboratory) was producing a substance effective against the parasite and further research should be conducted. From that point, investigations into OS-3153 escalated at Kitaken as well, and the strain was thoroughly preserved and managed. The Ōmura Grp. also prepared emergency measures in case of earthquakes or other natural disasters. As a further precaution to guarantee the preservation of this potent strain, samples were dispersed for storage in four private household refrigerators, including Prof. Ōmura’s and my own.
Research continued, and the antiparasitic substance produced by strain OS-3153 (MA-4680 at Merck & Co.) was found to be a new wide-spectrum antibiotic that was highly effective against a variety of parasites at only a trace amount. It was named “avermectin,” and the chemical structures of eight related compounds were elucidated.
During this exciting time, Merck & Co. offered to purchase strain OS-3153 for 300 million yen. The Kitaken Board of Trustees was very keen on the deal, but Prof. Ōmura declined the offer. In retrospect, Prof. Ōmura’s decisive refusal brought in about 20 billion yen to Kitaken from patent royalties, which funded the construction of the new hospital, established research funding for the Ōmura Laboratory and research subsidies, and played a major role in the reconstruction of Kitaken. For this and more, Ōmura’s decision should be applauded.
Consequently, researchers at Merck & Co. chemically modified avermectin to make “ivermectin.” This derivative was sold as a pharmaceutical for industrially important animals such as cattle and is the most widely administered veterinary drug today.
Ivermectin is highly effective against filarial roundworms in dogs. However, initial uses of the drug were fraught with unintended effects. When the drug was administered to dogs, macrofilariae residing in the blood vessels were killed, causing clogging in those blood vessels and consequently the death of the host dog. Learning from this, a new method to eliminate filariae was deduced. First, the macrofilariae were surgically removed, and ivermectin was administered when only microfilariae remained. There are also stories of Japanese veterinarians purchasing ivermectin in Hawaii because approval of the drug came much later in Japan.
Ivermectin was also found to be effective against parasites in humans. Through the support of Tropical Disease Research under the World Health Organization (WHO) and a handful of other research organizations, treatment and prevention research were expanded to humans based on experimental data from animals and the achievements in veterinary medicine. Under the product name “Mectizan,” the drug was provided free of charge in a plan to eradicate the tropical diseases onchocerciasis and lymphatic filariasis. In onchocerciasis, commonly known as River Blindness, the filarial roundworm uses the black fly as a vector to enter the subcutaneous tissue of the host and form nodules. From there, microfilaria larvae migrate to the eyes, ultimately leading to blindness. These devastating infectious diseases were highly prevalent in Africa’s tropical regions, and before the enactment of free administration of the medicine in 1987, tens of thousands of people became blind each year. Mectizan is effective as a treatment or preventative measure by taking it just once a year. Similarly, elephantiasis (lymphatic filariasis) is prevalent in the tropics and, as its name suggests, causes swelling and hardening of the skin to resemble that of an elephant. Good results were achieved using a combination drug therapy provided free of charge. The WHO predicts that by 2020, onchocerciasis and lymphatic filariasis will both be eradicated. In addition, this drug has also proven effective in Japan against strongyloidiasis, a disease seen in the Amami region and Okinawa, and scabies caused by the mite Sarcoptes scabiei, a disease prevalent in facilities for the elderly Mectizan is currently covered by health insurance.
Concluding remarks
Shibasaburo Kitasato was a leading candidate for the First Nobel Prize in Physiology or Medicine, but Behring, a joint researcher, was the sole recipient of that award. It was a great disappointment for everyone at Kitasato. I think for Prof. Ōmura, who esteemed Dr. Kitasato more than anyone, being awarded this Nobel Prize was deeply moving.
Prof. Ōmura has always told us that Dr. Kitasato is not just a treasure of both The Kitasato Institute and Kitasato University but also a treasure of Japan. I have led the mission to preserve and maintain materials documenting Dr. Kitasato’s research achievements in order to share his aspirations with the world. Furthermore, we built the Shibasaburo Kitasato Memorial Room so people from all over can learn about Dr. Kitasato. Two years from now, this memorial room will be expanded, and a newly renovated Shibasaburo Kitasato Memorial Hall is scheduled to open. I hope the readers come to visit.
When I was a student, the Japan Society for Bioscience, Biotechnology, and Agrochemistry published the first and second volumes of their journal: “KAGAKU TO SEIBUTSU .” These are still sitting on my bookshelf in their bindings today, and I am very grateful to be able to contribute to this enduring journal.
The description of the photograph that will be sent separately as an attachment is below.
1982 Kitasato Institute “Kitasato Memorial Award” celebration (June 7 1983)
Award Topic: Research on the Avermectin-producing and other actinomycetes
Members: (Front row) Prof. Ōmura, Dr. Oiwa, Dr. Iwai (Back row) Mr. Hinotozawa, Dr. Masuma, Dr. Takahashi 
Disclosure statement
No potential conflict of interest was reported by the author.
Notes
† This work is a translation of an original work in Japanese in the Japan Society for Bioscience, Biotechnology, and Agrochemistry http://doi.10.1271/kagakutoseibutsu.54.7